Evelyn Y. Chuang

University of California, San Francisco

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Pao‐Tien Chuang

University of California, San Francisco

Kuan Zhang

University of California, San Francisco

Ethan Chuang

University of California, San Francisco

Erica Yao

University of California, San Francisco

Biao Chen

Anhui University

Regan Volk

University of California, San Francisco

Katherine L. Hofmann

University of California, San Francisco

Balyn W. Zaro

Stanford Medicine

Cooperative Institutions

University of California, San Francisco

University of Montana

Universidad Católica de Santa Fe

Wuhan University

Harvard University

Molecular Research Institute

Cardiovascular Institute Hospital

University of California, Berkeley

Howard Hughes Medical Institute

Pacific Northwest National Laboratory

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Wnt5a–Vangl1/2 signaling regulates the position and direction of lung branching through the cytoskeleton and focal adhesions

PLoS Biology (2022)

Kuan Zhang Erica Yao Ethan Chuang Biao Chen Evelyn Y. Chuang

Lung branching morphogenesis requires reciprocal interactions between the epithelium and mesenchyme. How the lung branches are generated at a defined location and projected toward a specific direction remains a major unresolved issue. In this study, we investigated the function of Wnt signaling in lung branching in mice. We discovered that Wnt5a in both the epithelium and the mesenchyme plays an essential role in controlling the position and direction of lung branching. The Wnt5a signal is mediated by Vangl1/2 to trigger a cascade of noncanonical or planar cell polarity (PCP) signaling. In response to noncanonical Wnt signaling, lung cells undergo cytoskeletal reorganization and change focal adhesions. Perturbed focal adhesions in lung explants are associated with defective branching. Moreover, we observed changes in the shape and orientation of the epithelial sheet and the underlying mesenchymal layer in regions of defective branching in the mutant lungs. Thus, PCP signaling helps define the position and orientation of the lung branches. We propose that mechanical force induced by noncanonical Wnt signaling mediates a coordinated alteration in the shape and orientation of a group of epithelial and mesenchymal cells. These results provide a new framework for understanding the molecular mechanisms by which a stereotypic branching pattern is generated.

Mesenchyme

Cell polarity

10.1371/journal.pbio.3001759

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mTORC1 signaling facilitates differential stem cell differentiation to shape the developing murine lung and is associated with mitochondrial capacity

Nature Communications (2022)

Kuan Zhang Erica Yao Ethan Chuang Biao Chen Evelyn Y. Chuang

Abstract Formation of branched organs requires sequential differentiation of stem cells. In this work, we find that the conducting airways derived from SOX2 + progenitors in the murine lungs fail to form without mTOR complex 1 (mTORC1) signaling and are replaced by lung cysts. Proximal-distal patterning through transitioning of distal SOX9 + progenitors to proximal SOX2 + cells is disrupted. Mitochondria number and ATP production are reduced. Compromised mitochondrial capacity results in a similar defect as that in mTORC1-deficient lungs. This suggests that mTORC1 promotes differentiation of SOX9 + progenitors to form the conducting airways by modulating mitochondrial capacity. Surprisingly, in all mutants, saccules are produced from lung cysts at the proper developmental time despite defective branching. SOX9 + progenitors also differentiate into alveolar epithelial type I and type II cells within saccules. These findings highlight selective utilization of energy and regulatory programs during stem cell differentiation to produce distinct structures of the mammalian lungs.

SOX9

Progenitor

10.1038/s41467-022-34763-y

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Citations (4)